Severe viral respiratory infections in the pre‐COVID era: A 5‐year experience in two pediatric intensive care units in Italy

Abstract Background Viral respiratory infections are one of the main causes of hospitalization in children. Even if mortality rate is low, 2% to 3% of the hospitalized children need mechanical ventilation. Risk factors for admission to the pediatric intensive care unit (PICU) are well known, while few studies have described risk factors for invasive ventilator support and prolonged hospitalization. Methods A retrospective study including all patients aged between 2 and 18 months with a confirmed viral respiratory infection, requiring admission to PICU from September to March between 2015 and 2019, was conducted at Bambino Gesù Children's Hospital in Rome, Italy. Results One hundred ninety patients were enrolled, with a median age of 2.7 months; 32.1% had at least one comorbidity, mainly prematurity. The most frequent isolated viruses were RSV‐B, rhinovirus, and RSV‐A; 38.4% needed mechanical ventilation. This subgroup of patients had lower median birth weight compared with patients not requiring mechanical ventilation (2800 g vs. 3180 g, p = 0.02); moreover, comorbidities were present in 43.8% of intubated patients and in 24.8% of patients treated with non‐invasive ventilation (p = 0.006). Viral coinfection did not result to be a risk factor for mechanical support, while virus–bacteria coinfection was significantly associated with mechanical ventilation (p < 0.001). Similar risk factors were identified for prolonged hospitalization. Conclusions Early identification of patients who could have a sudden respiratory deterioration and need of mechanical ventilation is crucial to reduce complications due to orotracheal intubation and prolonged hospitalization in PICU. Further studies are needed to define high‐risk group of patients and to design targeted interventions.

moreover, comorbidities were present in 43.8% of intubated patients and in 24.8% of patients treated with non-invasive ventilation (p = 0.006). Viral coinfection did not result to be a risk factor for mechanical support, while virus-bacteria coinfection was significantly associated with mechanical ventilation (p < 0.001). Similar risk factors were identified for prolonged hospitalization.
Conclusions: Early identification of patients who could have a sudden respiratory deterioration and need of mechanical ventilation is crucial to reduce complications due to orotracheal intubation and prolonged hospitalization in PICU. Further studies are needed to define high-risk group of patients and to design targeted interventions.
bronchiolitis, intensive care units, pediatric, respiration, artificial, respiratory insufficiency, risk factors, viruses 1 | BACKGROUND Viral respiratory infections (VRIs) are one of the main causes of hospitalization in children. 1 Respiratory syncytial virus (RSV) is the most common identified pathogen in VRIs. Other common etiologies include rhinovirus, enterovirus, influenza virus, metapneumovirus, and parainfluenza virus. [2][3][4][5] From 2020, also SARS-COV2 has to be considered among the viruses responsible for respiratory infections in children. Coinfection with multiple viruses occurs in 20% to 40% of cases of severe pediatric VRIs. 4,6,7 Infants and toddlers are more frequently affected, with a peak incidence below 6 months of age. 8 Pediatric VRIs have a variable course, usually mild and self-limited in immunocompetent patients; however, symptoms like respiratory distress, apnoea, hypoxemia, and dehydration can occur, requiring hospitalization in 2% to 3% of cases. 8,9 Among the hospitalized patients, 2% to 3% needs mechanical ventilation. 9,10 However, mortality in hospitalized RSV-infected children in developed countries is less than 0.1%; this rate increases in patients affected by underlying chronic conditions. 8,11 Factors described to be associated with severe VRIs and ICU admission are age <6 weeks, low birth weight, prematurity (<37 week of gestation age), chronic lung disease, congenital heart disease, immunodeficiency, genetic/chromosomal abnormalities, cerebral palsy, and other neurological comorbidities. 12

| Study design and population
We conducted a retrospective descriptive study including all patients aged between 2 and 18 months with a confirmed viral infection, identified on a respiratory sample (i.e., naso-pharyngeal swab, tracheal swab, and/or broncho-alveolar lavage), requiring admission to PICUs from September to March between 2015 and 2019.
Patients requiring respiratory support for underlying diseases not related to the viral infection or those receiving antiviral therapy and/or intravenous immunoglobulin therapy (IVIG) within 48 h before symptoms onset were excluded.

| Data collection
Data were collected by physicians from patients' medical charts. Information collected for each patient included age at admission, gender, gestational age, birth weight, current weight, flu vaccination, previous VRIs, comorbidities, onset of respiratory symptoms, length of hospitalization, length of ICU hospitalization, administration of low flow oxygen or high-flow oxygen through nasal cannula (HFNC) before ICU admission, type of respiratory support received in ICU, and antiviral and antibiotic therapies. Microbiological results were reviewed for all the study population.
We defined patients experienced a "clinical cure" if both of the following criteria were met: (1) no signs or significantly reduced signs of respiratory distress and (2) no need of ventilator support or significantly reduced need of ventilation support after ICU discharge.
Death, ICU readmission within 48 h after discharge, or need for tracheostomy were considered as "clinical failure." All the collected data were uploaded on Research Electronic Data Capture (REDCap) database which is a secure web application for building and managing online surveys and databases, available at no charge to not-for-profit institutions. 13 All the data were analyzed anonymously.

| Statistical analysis
Patients were described according to demographic and clinical factors.
Collected data were presented as count and proportions (categorical data) or median and interquartile range (IQR, continuous data). Categorical data were compared using Chi-squared test or the Fisher's exact test, as appropriate. Continuous data were compared through the Wilcoxon rank-sum test.

| RESULTS
During the study period, 190 patients required PICUs admission for VRIs. Patients were more commonly female (n = 98, 51.6%), with a median age of 2.7 months (IQR: 1.5-7.9) and a median weight of 5000 g (IQR: 4040-7000) at the time of hospital admission (Table 1).

| Antimicrobials
Overall, 264 antibiotic prescriptions were issued to 172 patients

| Patient outcome
The

| Risk factors for mechanical ventilation
As shown in Table 2, patients with low birth weight and with at least one comorbidity required more frequently mechanical ventilation. In Only bacterial isolation resulted to be risk factor for prolonged mechanical ventilation: patients with bacterial isolation more T A B L E 2 Demographic, clinical, and microbiological differences between patients who required mechanical ventilation and patients receiving non-invasive ventilation In our cohort, the median birth weight was 3080 g (range 2600-3470 g), with a significant difference (p = 0.02) between patients who required mechanical ventilation and patients who did not. In line with our findings, Papoff et al in 2011 found that infants with severe bronchiolitis had a median birth weight of 2.8 AE 0.4 kg, significantly lower than infants with mild-to-moderate forms not requiring ventilator support. 15 As hypothesized by Barker et al, the adverse environment in utero, which affects the weight gain of the fetus, plays a role also in the reduced growth of the airways, predisposing to bronchiolar obstruction during viral infections. 16 Among the 61 patients affected by comorbidities, 32.8% of all patients were born prematurely and 31.1% had a congenital heart disease (CHD). Even if patients with at least a comorbidity had a significantly higher need of mechanical respiratory support, neither prematurity nor CHD were statistically associated with need for mechanical ventilation, probably due to the small size of the sample.
These findings confirms data from previous studies; Mecklin et al in 2017 showed higher risk for respiratory support in born preterm patients at less than 37 weeks and patients affected by CHD in a cohort of 105 infants with VRIs. 17 Overall, RSV was the most frequently detected pathogen, identified in the respiratory tract of 48% of our patients. According to the literature, most children have been infected with RSV at least once by 2 years of age and present a self-limited course of disease; however, approximately 2% to 3% of infants younger than 12 months are hospitalized with RSV infection each year in the United States. 1 Noteworthy, in our cohort, no differences in viral distribution were noted between patients who needed mechanical ventilation and patients who did not.
Interestingly, the peak period for PICU admission due to VRI occurred between December and January in each season; this reflects the frequency of RSV, which generally peaks in Europe in the early winter season. 18 Detection of viral coinfections occurred in 34.7% of cases in our cohort; the identification of multiple viruses in the respiratory tract did not result to be a risk factor for orotracheal intubation but seemed to be related to a longer hospitalization. Rates of viral coinfection reported in other studies range from 6% to more than 30%, but the correlation with greater disease severity and longer length of ICU staying is unclear to date. Coleman et al observed a similar duration of respiratory support and PICU hospitalization in patients infected with a single virus compared with patients infected with more than one virus. 19 These data are consistent with the results published by Ghazaly and Nadel that did not find out clinical or radiologic differences between single and multiple VRIs in a cohort of 422 children. 13 Other studies show, however, conflicting data; in particular, recently, the multivariable regression analysis of a study on 477 infants admitted to the PICU with one or multiple organisms showed an association between coinfections and higher odds of longer PICU stay, prolonged mechanical ventilation, central line requirement, and bacterial coinfection. 20 In our study, bacterial coinfections were identified in 15.3% of children from cultural exams of the tracheal aspirates (TA) and bronchoalveolar lavages (BAL); we demonstrated that viral-bacterial coinfection is a risk factor for mechanical ventilation (p < 0.001). This prevalence was lower than previously shown in other studies that reported bacterial coinfections in 26% to 45% of children with bronchiolitis admitted to PICU. 21,22 In our cohort, the rate of bacterial coinfection could be underestimate because only mechanically ventilated patients or patients with tracheostomy were tested for a bacterial coinfection.
We do not routinely carry out throat cultures in infants without orotracheal intubation or tracheostomy. Consistently with other studies, in our setting, H. influenzae was the most frequent isolated bacterium. 23 Despite the low rate of bacterial coinfection, antibiotics were prescribed in 90.5% of our patients, with 43.6% of patients receiving more than one antibiotic. Clarithromycin was the most common used antibiotic, followed by ceftriaxone and amoxicillin/clavulanate. The overprescription of antibiotics is probably due to the severity of the patients and to the difficulty to distinguish between a viral or bacterial respiratory infection before microbiological results are available. Bacterial pneumonia is usually diagnosed by a combination of clinical signs and symptoms, laboratory markers, and chest radiography; 53.7% of patients in our cohort had elevated values of inflammatory markers at admission, and in 59.7% of cases, chest X-ray showed parenchymal opacities, thus making it difficult to exclude a bacterial etiology. However, the misuse and abuse of antibiotics is a challenging problem in Italy and all over the world thus antibiotic stewardship programs should aim to identify feasible targets to monitor and modify the prescription patterns in these settings. 24 Antivirals were prescribed in the 17.8% of patients. In the last few years, updated guidelines on the management of bronchiolitis have been published, but none focused on critically ill infants. The American Academy of Pediatrics guidelines recommend only supportive therapy, such as oxygen therapy for hypoxemia, respiratory support, and maintenance of hydration. 25 Continuous positive air pressure (CPAP) has traditionally been used as the first-line respiratory support in severe VRIs. 26 Our hospital has a long and wide experience in the use of Helmet CPAP, that is now available both in emergency and pediatric wards. Early CPAP has been associated with a lower risk of intubation, a faster normalization of heart and respiratory rates, and an increase in the PaO 2 /FiO 2 ratio already after the first hour of treatment. 27 More recently, the administration of heated and humidified oxygen with HFNC has been shown to play an important role in reducing respiratory work, improving gas exchanges and avoiding endotracheal intubation. 28  Based on these findings, 27 patients of our cohort received oral ribavirin, combined in 19 patients with IVIG. Although no conclusions can be drawn in terms of efficacy because of a case-control study was not performed, we can state that none of these patients died or had lifethreatening side effects. One patient experienced an important increase of creatine phosphokinase blood level; however, this adverse event has never been described before during the treatment with ribavirin. A single-case report of an adult patient presenting with rhabdomyolysis after the association with daptomycin, pegylated interferon α-2b, and ribavirin was described by Colomba et al, but the author concluded that ribavirin did not play any role in the pathogenesis of the myopathy in that patient. 31 Therefore, even though it is difficult to assess the cause of rhabdomyolysis in our patient, it appears unlikely to be related to the treatment with ribavirin.
Severe bronchiolitis requiring admission to PICU is frequently associated with morbidity; however, the mortality rate is low. In 2005, Panickar et al reported that mortality rates have fallen in the last three decades from 21.5 to 1.8 per 100.000 children below 12 months, reflecting improvements in pediatric intensive care. 32 In a more recent review, death due to respiratory failure in bronchiolitis ranges from 2.9 (United Kingdom) to 5.3 (United States) deaths per 100.000 children. 33 In our cohort, similar to data reported by Ghazaly and Nadel, death occurred in a very low rate of patients (1%). 13 In conclusion, demographic and clinical variables can help to identify children affected by VRI at risk for worse outcome. Further studies are needed to design targeted interventions on high-risk patient groups to reduce the risk of complications related to orotracheal intubation and prolonged hospitalization in intensive care settings.